全文获取类型
收费全文 | 2064篇 |
免费 | 139篇 |
专业分类
2203篇 |
出版年
2021年 | 11篇 |
2020年 | 7篇 |
2019年 | 10篇 |
2018年 | 19篇 |
2017年 | 16篇 |
2016年 | 14篇 |
2015年 | 41篇 |
2014年 | 38篇 |
2013年 | 122篇 |
2012年 | 87篇 |
2011年 | 81篇 |
2010年 | 56篇 |
2009年 | 54篇 |
2008年 | 112篇 |
2007年 | 119篇 |
2006年 | 113篇 |
2005年 | 112篇 |
2004年 | 139篇 |
2003年 | 96篇 |
2002年 | 106篇 |
2001年 | 71篇 |
2000年 | 74篇 |
1999年 | 61篇 |
1998年 | 27篇 |
1997年 | 32篇 |
1996年 | 22篇 |
1995年 | 34篇 |
1994年 | 33篇 |
1993年 | 25篇 |
1992年 | 54篇 |
1991年 | 53篇 |
1990年 | 57篇 |
1989年 | 21篇 |
1988年 | 47篇 |
1987年 | 28篇 |
1986年 | 25篇 |
1985年 | 24篇 |
1984年 | 16篇 |
1983年 | 16篇 |
1982年 | 14篇 |
1981年 | 11篇 |
1980年 | 8篇 |
1979年 | 13篇 |
1978年 | 6篇 |
1977年 | 7篇 |
1976年 | 11篇 |
1975年 | 8篇 |
1974年 | 16篇 |
1973年 | 7篇 |
1968年 | 6篇 |
排序方式: 共有2203条查询结果,搜索用时 15 毫秒
91.
Toshikazu Ushijima Tomoko Nomoto Takashi Sugimura David E. Housman Minako Nagao 《Mammalian genome》1998,9(12):1008-1012
Mapping of genetic suppressors, modifiers, and quantitative trait loci (QTLs) requires genetic markers that can be efficiently
and inexpensively genotyped for a large number of individuals. To isolate rat genetic markers suitable for this purpose, representational
difference analysis (RDA) was performed with amplicons prepared by PCR with the B1 repetitive sequence used as the primer
(B1-amplicons). In total, 48 polymorphic DNA fragments were isolated by five series of RDA, subtracting the B1-amplicons prepared
from an ACI/N (ACI) rat from those prepared from BUF/Nac (BUF), and vice versa. All the polymorphic fragments detected ``presence-or-absence'
polymorphisms with B1-amplicons prepared from ACI, BUF, and their F2 progeny, and each fragment was linkage mapped. Dot-blotting amplicons onto filters at a high density and hybridization of
the filters with these B1-RDA markers made it possible to genotype a large number of rats simultaneously for multiple loci.
These B1-RDA markers were polymorphic between two given inbred strains of rat at frequencies between 30% and 70%. This is
the first report on the isolation of B1-RDA markers among inbred strains of rats.
Received: 15 July 1998 / Accepted: 18 August 1998 相似文献
92.
Itoh T Suzuki T Nishikawa A Furukawa F Takahashi M Xue W Sofuni T Hayashi M 《Mutation research》2000,468(1):19-25
2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), a heterocyclic amine found in cooked meat, is a strong mutagen in the Salmonella/microsome assay and was proven to be a hepatocarcinogen in rodents. We used the lacI transgenic (Big Blue(R)) mouse to investigate MeIQx genotoxicity in vivo. lacI mutant frequencies were examined in liver and colon after single intragastric administration of MeIQx (males) or 12 weeks of feeding in the diet (males and females). Micronucleus induction was monitored in the peripheral blood and cell proliferating activity was monitored by proliferating cell nuclear antigen (PCNA) immunostaining, but only after the intragastric administration. Intragastric treatment with MeIQx (100 mg/kg) did not increase mutant frequency (MF) in liver or colon but it did induce a slight but statistically significant increase in the incidence of micronucleated reticulocytes 48 h after the treatment. No apparent increase in PCNA-positive foci was observed in any of tissues analyzed 14 days after the treatment. Administration of MeIQx (300 ppm) in diet for 12 weeks, however, caused MF increases in liver and colon in male and female mice, with greater increases in the females. An increase was also obvious after 4 weeks, but only in females. The sex difference in MF is consistent with the fact that female mice are more susceptible to MeIQx carcinogenesis. These results demonstrated that in the transgenic mouse mutation assay, long-term feeding of MeIQx was more effective than single gastric exposures in revealing the compound's mutagenicity in the target organs of carcinogenicity and that sex differences in susceptibility can also be observed. 相似文献
93.
Nishikawa H Oishi S Fujita M Watanabe K Tokiwa R Ohno H Kodama E Izumi K Kajiwara K Naitoh T Matsuoka M Otaka A Fujii N 《Bioorganic & medicinal chemistry》2008,16(20):9184-9187
Emergence of multi-drug resistant HIV-1 is a serious problem for AIDS treatment. Recently, the virus-cell membrane fusion process has been identified as a promising target for the development of novel drugs against these resistant variants. In this study, we identified a 29-residue peptide fusion inhibitor, SC29EK, which shows activity comparable to the previously reported inhibitor SC35EK. Some residues in SC29EK not required for interaction with virus gp41 heptad repeat 1 (HR1) were replaced with a non-proteinogenic amino acid, 2-aminoisobutyric acid (Aib), to stabilize the alpha-helix structure and to provide resistance to peptidases. 相似文献
94.
95.
Toshio Watanabe Toshihisa Takeuchi Osamu Handa Yasuhisa Sakata Tetsuya Tanigawa Masatsugu Shiba Yuji Naito Kazuhide Higuchi Kazuma Fujimoto Toshikazu Yoshikawa Tetsuo Arakawa 《PloS one》2015,10(4)
Background
Low-dose aspirin (LDA) frequently causes small bowel injury. While some drugs have been reported to be effective in treating LDA-induced small intestinal damage, most studies did not exclude patients with mild damage thought to be clinically insignificant.Aim
We conducted a multicenter, randomized, double-blind, placebo-controlled trial to assess the efficacy of a high dose of rebamipide, a gastroprotective drug, for LDA-induced moderate-to-severe enteropathy.Methods
We enrolled patients who received 100 mg of enteric-coated aspirin daily for more than 3 months and were found to have more than 3 mucosal breaks (i.e., erosions or ulcers) in the small intestine by capsule endoscopy. Eligible patients were assigned to receive either rebamipide 300 mg (triple dose) 3 times daily or placebo for 8 weeks in a 2:1 ratio. Capsule endoscopy was then repeated. The primary endpoint was the change in the number of mucosal breaks from baseline to 8 weeks. Secondary endpoints included the complete healing of mucosal breaks at 8 weeks and the change in Lewis score (an endoscopic score assessing damage severity) from baseline to 8 weeks.Results
The study was completed by 38 patients (rebamipide group: n = 25, placebo group: n = 13). After 8 weeks of treatment, rebamipide, but not placebo, significantly decreased the number of mucosal breaks (p = 0.046). While the difference was not significant (p = 0.13), the rate of complete mucosal break healing in the rebamipide group (32%, 8 of 25) tended to be higher than that in the placebo group (7.7%, 1 of 13). Rebamipide treatment significantly improved intestinal damage severity as assessed by the Lewis score (p = 0.02), whereas placebo did not. The triple dose of rebamipide was well tolerated.Conclusions
High-dose rebamipide is effective for the treatment of LDA-induced moderate-to-severe enteropathy.Trial Registration
UMIN Clinical Trials Registry UMIN000003463 相似文献96.
Yoshiaki Tsuda Haruo Sawada Takafumi Ohsawa Katsuhiro Nakao Hiroki Nishikawa Yuji Ide 《Tree Genetics & Genomes》2010,6(3):377-387
We evaluated the genetic structure of 16 Betula maximowicziana populations in the Chichibu mountain range, central Japan, located within a 25-km radius; all but two populations were at
altitudes of 1,100–1,400 m. The results indicate the effects of geographic topology on the landscape genetic structure of
the populations and should facilitate the development of local-scale strategies to conserve and manage them. Analyses involving
11 nuclear simple sequence repeat loci showed that most populations had similar intrapopulation genetic diversity parameters.
Population differentiation (F
ST = 0.021, G′ST = 0.033) parameters for the populations examined were low but were relatively high compared to those obtained in a previous
study covering populations in a much larger area with a radius of approximately 1,000 km (F
ST = 0.062, G′ST = 0.102). Three populations (Iriyama, Kanayamasawa, and Nishizawa) were differentiated from the other populations by Monmonier’s
and spatial analysis of molecular variance algorithms or by STRUCTURE analysis. Since a high mountain ridge (nearly 2,000 m)
separates the Kanayamasawa and Nishizawa populations from the other 14 populations and the Kanayamasawa and Nishizawa populations
are themselves separated by another mountain ridge, the genetic structure appears to be partly due to mountain ridges acting
as genetic barriers and restricting gene flow. However, the Iriyama population is genetically different but not separated
by any clear geographic barrier. These results show that the landscape genetic structure is complex in the mountain range
and we need to pay attention, within landscape genetic studies and conservation programs, to geographic barriers and local
population differentiation. 相似文献
97.
Fu-Zheng Wei Ziyang Cao Xi Wang Hui Wang Mu-Yan Cai Tingting Li Naoko Hattori Donglai Wang Yipeng Du Boyan Song Lin-Lin Cao Changchun Shen Lina Wang Haiying Wang Yang Yang Dan Xie Fan Wang Toshikazu Ushijima Ying Zhao Wei-Guo Zhu 《Autophagy》2015,11(12):2309-2322
Macroautophagy is an evolutionarily conserved cellular process involved in the clearance of proteins and organelles. Although the autophagy regulation machinery has been widely studied, the key epigenetic control of autophagy process still remains unknown. Here we report that the methyltransferase EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) epigenetically represses several negative regulators of the MTOR (mechanistic target of rapamycin [serine/threonine kinase]) pathway, such as TSC2, RHOA, DEPTOR, FKBP11, RGS16 and GPI. EZH2 was recruited to these genes promoters via MTA2 (metastasis associated 1 family, member 2), a component of the nucleosome remodeling and histone deacetylase (NuRD) complex. MTA2 was identified as a new chromatin binding protein whose association with chromatin facilitated the subsequent recruitment of EZH2 to silenced targeted genes, especially TSC2. Downregulation of TSC2 (tuberous sclerosis 2) by EZH2 elicited MTOR activation, which in turn modulated subsequent MTOR pathway-related events, including inhibition of autophagy. In human colorectal carcinoma (CRC) tissues, the expression of MTA2 and EZH2 correlated negatively with expression of TSC2, which reveals a novel link among epigenetic regulation, the MTOR pathway, autophagy induction, and tumorigenesis. 相似文献
98.
Kobayashi T Nishikawa T Hattori S Yoshida N Takagi T Watanabe H Hori H Nagai Y 《Protein expression and purification》2001,22(1):45-51
We developed a simple and effective method for the systematic separation and purification of human polymorphonuclear leukocyte (PMN) proteinases, elastase, gelatinase (matrix metalloproteinase 9, type IV collagenase), and collagenase (matrix metalloproteinase 8), derived from the extracts of hollow fiber dialyzers that had been utilized in the treatment of patients with renal failure. The fraction containing elastase was grossly separated from that containing gelatinase and collagenase by heparin-Sepharose chromatography and purified in an aprotinin column. The remaining two enzymes were then separated using the gelatin-Sepharose column after gel chromatography following ammonium sulfate precipitation. Gelatinase and collagenase were further purified by gelatin-Sepharose chromatography as a latent form and by collagen-Sepharose chromatography as an activated form. This novel method offers procedural advantages over existing methods that separate PMNs from the whole blood of volunteers for experimental research purposes. 相似文献
99.
Tadateru Nishikawa Noboru Ishiyama Feng Wang Mitsuhiko Ikura 《Biomolecular NMR assignments》2017,11(1):21-24
α-Catenin is a filamentous actin (F-actin) binding protein that links the classical cadherin–catenin complex to the actin cytoskeleton at adherens junctions (AJs). Its C-terminal F-actin binding domain is required for regulating the dynamic interaction between AJs and the actin cytoskeleton during tissue development. Thus, obtaining the molecular details of this interaction is a crucial step towards understanding how α-catenin plays critical roles in biological processes, such as morphogenesis, cell polarity, wound healing and tissue maintenance. Here we report the backbone atom (1HN, 15N, 13Cα, 13Cβ and 13C′) resonance assignments of the C-terminal F-actin binding domain of αN-catenin. 相似文献
100.
Kawahito Y Ichinose S Sano H Tsubouchi Y Kohno M Yoshikawa T Tokunaga D Hojo T Harasawa R Nakano T Matsuda K 《Biochemical and biophysical research communications》2008,369(2):561-566
Mycoplasma fermentans has been suspected as one of the causative pathogenic microorganisms of rheumatoid arthritis (RA) however, the pathogenic mechanism is still unclear. We, previously, reported that glycolipid-antigens (GGPL-I and III) are the major antigens of M. fermentans. Monoclonal antibody against the GGPL-III could detect the existence of the GGPL-III antigens in synovial tissues from RA patients. GGPL-III antigens were detected in 38.1% (32/84) of RA patient’s tissues, but not in osteoarthritis (OA) and normal synovial tissues. Immunoelectron microscopy revealed that a part of GGPL-III antigens are located at endoplasmic reticulum. GGPL-III significantly induced TNF-α and IL-6 production from peripheral blood mononulear cells, and also proliferation of synovial fibroblasts. Further study is necessary to prove that M. fermentans is a causative microorganism of RA; however, the new mechanisms of disease pathogenesis provides hope for the development of effective and safe immunotherapeutic strategies based on the lipid-antigen, GGPL-III, in the near future. 相似文献